CN110680822A - 一种人参二醇、人参三醇的pcc氧化产物的应用 - Google Patents
一种人参二醇、人参三醇的pcc氧化产物的应用 Download PDFInfo
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- PVLHOJXLNBFHDX-XHJPDDKBSA-N Panaxadiol Chemical compound C[C@]1([C@H]2CC[C@@]3([C@@H]2[C@H](O)C[C@H]2[C@]3(CC[C@H]3C(C)(C)[C@@H](O)CC[C@@]32C)C)C)CCCC(C)(C)O1 PVLHOJXLNBFHDX-XHJPDDKBSA-N 0.000 title claims abstract description 17
- SYFJYASKXNAXKC-UHFFFAOYSA-N Panaxadiol Natural products CC1(C)CCCC(O1)C2CCC3(C)C2C(O)CC4C5(C)CCC(O)C(C)(C)C5CCC34C SYFJYASKXNAXKC-UHFFFAOYSA-N 0.000 title claims abstract description 17
- QFJUYMMIBFBOJY-UXZRXANASA-N Panaxatriol Chemical compound C[C@]1([C@H]2CC[C@@]3([C@@H]2[C@H](O)C[C@H]2[C@]3(C[C@@H](O)[C@H]3C(C)(C)[C@@H](O)CC[C@@]32C)C)C)CCCC(C)(C)O1 QFJUYMMIBFBOJY-UXZRXANASA-N 0.000 title claims abstract description 16
- VIXIMKLMEZTTTC-UHFFFAOYSA-N Panaxatriol Natural products CC1(C)CCCC(O1)C2CCC3(C)C2C(O)CC4C5(C)CCC(O)C(C)(C)C5C(O)CC34C VIXIMKLMEZTTTC-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 230000003647 oxidation Effects 0.000 title claims abstract description 14
- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 14
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- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 3
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
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Abstract
本发明公开了一种人参二醇、人参三醇的PCC氧化产物的应用;用于治疗心脑血管疾病,本发明有益效果是从三七皂苷为原材料制备获取的PCC氧化产物,用于生产一种毒性小、活性强、生物利用度高的用于治疗心脑血管疾病的药品。
Description
技术领域
本发明涉及心血管医药领域,尤其涉及是一种人参二醇、人参三醇的PCC氧化产物的应用。
背景技术
三七是主产云南的国际瞩目的明星药用植物,现有含三七的产品,多使用三七总皂苷(比如血塞通),或使用三七提取物,甚至直接使用三七粉,科技含量不高、附加值低。其中,血塞通(三七总皂苷)已成为预防和治疗心脑血管疾病的基础药物。药物代谢动力学研究表明血塞通可以在体内发生代谢,典型代谢为脱糖至生成苷元,这表明其发生疗效的主要成分为苷元或苷元衍生物,根据C-6位上是否连有羟基,将三七皂苷分为人参二醇型皂苷和人参三醇型皂苷。有望制成毒性小,活性强,生物利用度高的治疗心脑血管疾病药物,并且将促进三七作用机制的阐明,有望提高三七的产品附加值。
发明内容
本发明的目的在于提供一种人参二醇、人参三醇的PCC氧化产物的应用,以提高三七皂苷为原料生成的衍生物工业获得一种毒性小,活性强,生物利用度高的治疗心脑血管疾病的药品。
为实现上述目的,本发明提供如下技术方案:
一种人参二醇、人参三醇的PCC氧化产物的应用,治疗心脑血管疾病药物的应用。
进一步地,药物浓度为0.1—1000μmol/L。
进一步地,最佳浓度为8umol/L。
本发明的技术效果和优点:
(1)毒性小,活性强,生物利用度高的治疗心脑血管疾病药物。
(2)三七的原料成本较低,可提高三七的产品附加值,原材料获取较为容易。
(3)通过三七皂苷的降解制备人参二醇和人参三醇,并进一步采用PCC氧化法制备人参二醇和人参三醇衍生物后均具有舒张心脑血管的活性。
附图说明
图1为本发明提供的化合物1-5结构式。
图2为本发明提供的BA血管累积量效曲线。
图3为本发明提供的CA血管累积量效曲线。
具体实施方式
下面将结合本发明实施例中的具体应用,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例
本实施例进一步地结合试验数据及案例试验证明,化合物的用于心血管治疗的药理特性,由三七制备的衍生物的化学结构式如图1所示,
人参二醇和人参三醇的制备
称取三七总皂苷100g,置于1000ml的圆底烧瓶中,加入36.5%浓盐酸500ml,室温条件下搅拌24小时,抽滤得到粗产物45g。固体粗产物用100-200目硅胶1:1拌样上样,经200-300目硅胶分离,依次用石油醚-乙酸乙酯(10:1→10:3)梯度洗脱,薄层色谱(TCL)检测,依次得到化合物1(4.25g)和化合物2(2.5g)。
化合物1
白色粉末,C30H52O3,
1HNMR(CDCl3,500MHz)δppm:3.52(1H,d,H-12),3.19(1H,s,H-3),1.24(3H,s,H-26),1.21(3H,s,H-28),1.18(3H,s,H-21),0.97(3H,s,H-29),0.97(3H,s,H-18),0.87(3H,s,H-19),0.77(3H,s,H-30);
13CNMR(CDCl3,125MHz)δppm:78.93(C-3),76.67(C-20),73.10(C-25),69.94(C-12),55.87(C-5),54.74(C-17),51.24(C-14),49.93(C-9),49.16(C-13),39.79(C-8),38.93(C-1),38.87(C-4),37.13(C-10),36.46(C-24),35.76(C-22),34.88(C-7),33.05(C-26),31.16(C-15),30.57(C-11),28.05(C-28),27.49(C-2),27.12(C-27),25.19(C-16),19.42(C-21),18.32(C-6),17.07(C-30),16.29(C-23),16.14(C-19),15.63(C-18),15.37(C-29).
化合物2
白色粉末,C30H52O4,
1HNMR(CDCl3,500MHz)δppm:3.52(1H,d,H-12),1.25(3H,s,H-27),1.22(3H,s,H-26),1.18(3H,s,H-21),1.17(3H,s,H-28),1.06(3H,s,H-18),0.97(3H,s,H-29),0.92(3H,s,H-19),0.89(3H,s,H-30);
13CNMR(CDCl3,125MHz)δppm:78.61(C-3),76.64(C-20),73.18(C-25),69.82(C-12),68.77(C-6),61.14(C-5),54.66(C-17),51.04(C-14),49.39(C-9),48.74(C-13),47.07(C-7),41.00(C-8),39.26(C-4),39.18(C-10),38.67(C-1),36.42(C-24),35.71(C-22),33.03(C-26),31.12(C-15),30.87(C-28),30.37(C-11),27.13(C-27),27.07(C-2),25.14(C-16),19.39(C-21),17.18(C-30),17.16(C-19),17.03(C-18),16.25(C-23),15.50(C-29).
称取1g化合物1置于10ml茄型烧瓶中,加入2mol/LKOH甲醇溶液50ml,于90℃加热回流2小时,硅胶TCL检测至原料点消失停止反应,冷却至室温。用2mol/LHCL溶液中和至中性,减压蒸干,加入20ml水后用氯仿萃取三次(50ml×3),合并有机相得到固体860mg。经硅胶柱色谱纯化,石油醚-乙酸乙酯(19:1-17:3)梯度洗脱得到化合物3,产率86.3%。
化合物3
白色粉末,C30H48O4,
1HNMR(CDCl3,500MHz)δppm:3.64(1H,s,H-12),1.27(3H,s,H-27),1.22(3H,s,H-26),1.18(3H,s,H-21),1.18(3H,s,H-28),1.10(3H,s,H-18),1.04(3H,s,H-29),0.96(3H,s,H-19),0.83(3H,s,H-30);
13CNMR(CDCl3,125MHz)δppm:214.54(C-3),211.01(C-6),76.57(C-20),73.32(C-25),69.21(C-12),65.36(C-5),54.81(C-17),52.46(C-7),51.01(C-14),49.82(C-9),48.94(C-13),46.98(C-8),46.18(C-10),43.39(C-4),41.18(C-1),36.39(C-24),35.65(C-22),33.92(C-2),33.02(C-26),31.12(C-15),30.94(C-11),27.12(C-27),24.83(C-16),21.62(C-28),19.40(C-21),17.25(C-30),16.41(C-19),16.22(C-18),15.76(C-23),14.15(C-29).
人参二醇PCC氧化产物的制备
将100g三氧化铬迅速加入到184ml,6molL-1盐酸中并不断搅拌,5min后将均相体系冷却至0℃,在至少10min内小心加入79.1mg吡啶。将反应体系重新冷却至0℃,得橙黄色固体,过滤,真空干燥lh,得PCC180g。
称取人参二醇(500mg,1eq,1.09mmol)加入到50ml二颈瓶中,先加入15mlCH2Cl2充分溶解后,再称取PCC(3eq,701.77mg),15mlCH2Cl2充分溶解搅拌均匀后,在搅拌的情况下快速加入到二颈瓶中,用TLC板跟踪反应过程,反应2小时后,TLC跟踪反应过程,原料消失后停止反应,用100-200目硅胶快速过滤,溶剂用乙酸乙酯冲洗,乙酸乙酯减压浓缩后,柱色谱纯化得化合物4。
化合物4
白色粉末,
1HNMR(500MHz,CDCl3)δ:0.86(3H,s,H-19),0.97(3H,s,H-30),1.00(3H,s,H-28),1.02(3H,s,H-18),1.06(3H,s,H-29),1.18(3H,s,H-26),1.21(3H,s,H-27),1.26(3H,s,H-21),3.52-3.57(1H,m,CH-12);
13CNMR(CDCl3,125MHz)δ:217.9(C-3),76.6(C-20),73.3(C-25),69.9(C-12),55.2(C-17),54.5(C-13),51.1(C-14),49.2(C-9),49.1(C-5),47.3(C-4),39.6(C-1),39.6(C-8),36.7(C-10),36.3(C-24),35.6(C-2),34.1(C-22),34.0(C-7),33.0(C-27),31.0(C-15),30.7(C-11),27.0(C-26),26.6(C-29),25.0(C-16),20.9(C-28),19.6(C-6),19.3(C-21),16.8(C-30),16.1(C-23),15.9(C-18),15.2(C-19).
人参三醇PCC氧化产物
将100g三氧化铬迅速加入到184ml,6molL-1盐酸中并不断搅拌,5min后将均相体系冷却至0℃,在至少10min内小心加入79.1mg吡啶。将反应体系重新冷却至0℃,得橙黄色固体,过滤,真空干燥lh,得PCC180g。
称取人参三醇(500mg,1eq,1.09mmol)加入到50ml二颈瓶中,先加入15mlCH2Cl2充分溶解后,再称取PCC(3eq,701.77mg),15mlCH2Cl2充分溶解搅拌均匀后,在搅拌的情况下快速加入到二颈瓶中,用TLC板跟踪反应过程,反应2小时后,TLC跟踪反应过程,原料消失后停止反应,用100-200目硅胶快速过滤,溶剂用乙酸乙酯冲洗,乙酸乙酯减压浓缩后,柱色谱纯化得化合物5。
化合物5
白色粉末,
1HNMR(500MHz,CDCl3)δ:0.97(3H,s);1.02(3H,s);1.16(3H,s);1.08(3H,s);1.16(3H,s);1.23(3H,s);1.25(3H,s);1.46(3H,s);2.55(2H,d,H-7);3.61(1H,m,H-12);6.40(1H,br.s,-OH);
13CNMR(CDCl3,125MHz)δ:41.97(t,C-1),34.72(t,C-2),215.37(s,C-3),44.20(s,C-4),66.14(d,C-5),211.85(s,C-6),53.27(t,C-7),47.78(s,C-8),49.73(d,C-9),46.98(s,C-10),31.93(t,C-11),70.02(d,C-12),50.61(d,C-13),51.82(s,C-14),31.73(t,C-15),25.64(t,C-16),55.60(d,C-17),17.23(q,C-18),16.56(q,C-19),78.20(s,C-20),20.21(q,C-21),36.45(t,C-22),17.03(t,C-23),37.19(t,C-24),74.13(s,C-25),33.84(q,C-26),27.93(q,C-27),22.43(q,C-28),24.97(q,C-29),18.05(q,C-30)。
PCC氧化物的试剂及药物的配制
血栓素受体激动剂U46619:分子量为350.5,真空条件下使U46619中的溶剂乙酸乙酯溶液挥干,再用无水乙醇溶解U46619得母液(2mM),-20℃保存.临用前用三蒸水稀释至所需浓度。
将受试药物设成摩尔浓度:0.1μmol/L,0.3μmol/L,1μmol/L,3μmol/L,10μmol/L,30μmol/L,100μmol/L,300μmol/L和1000μmol/L的剂量组,利用累积浓度加入法进行活性检测,具体配制加入方法见下表1。
表1受试样品摩尔浓度配制表
MOPS-PSS缓冲液含(1L):NaCl81.8g,KCl3.5g,MOPS4.2g,Na2HPO4.12H2O4.3g,Na2-EDTA.2H2O0.07g,MgSO4.7H2O12.3g,CaCl25.5g,Glucose.H2O1.1g.
MOPS-KPSS缓冲液含(1L):NaCl49.5g,KCl44.8g,MOPS4.2g,Na2HPO4.12H2O4.3g,Na2-EDTA.2H2O0.07g,MgSO4.7H2O12.3g,CaCl25.5g,Glucose.H2O1.1g.
药理实验过程
血管环制备与平衡
大鼠用10%的乌拉坦(10mL/kg)麻醉致死,并迅速取出心脏和大脑置于4℃MOPS-PSS液中.体式解剖显微镜下,用显微手术器械将心右冠状动脉(CA)和脑基底动脉(BA)取出并且将周围组织分离干净,CA和BA剪成长度约1mm血管环备用。
体式解剖显微镜下,用2根长1.5cm,直径60um的钨丝穿过血管环(注意尽量不要损伤血管内皮等),分别挂置于DMT浴槽中,浴槽中盛MOPS-PSS工作液,恒温37℃并且持续通入O2。
待血管环全部置于DMT上后,调节微调装置,分别给CA和BA约1mN、1.5mN的预负荷。
每隔20min换1次MOPS-PSS(37℃)工作液,每次5ml,平衡三次后,然后更换MOPS-KPSS工作液(含60mMK+)5mL检测血管环活性,检测两次,每次5min。当收缩力为预负荷2倍左右时认为活性合格,用MOPS-PSS(37℃)工作液洗涤2-3次后再加入5mLMOPS-PSS(37℃)工作液平衡后用于实验。然后按照预先计算的给药体积加药。
CA、BA平衡并检测血管环活性合格后,加入U46619收缩血管,待收缩达到最大值且平衡后,每隔10min累积加入配置好的药物。同一药物的不同剂量在同一根血管环上检测并用PowerLAB数据记录和分析系统采集数据。每一个受试药物取8根血管环进行重复试验。
统计学数据处理分析
采用SigmaStat10.0统计分析软件对数据进行分析处理,采用SigmaPlot利用均值和标准误作图表示各个受试药物对CA和BA的舒张作用的影响;并模拟计算半数有效浓度(EC50),相对张力值计算公式为:相对张力值=(X-平衡值)/(U4收缩值-平衡值)×100%。
以下各图表示累积量效曲线图2-3所示,
横坐标表示受试药物浓度,
纵坐标表示受试药物对血管的相对张力值,
相对张力值越小表示药物对血管的舒张活性越好,相对张力值小于50%时,认为有一定程度的血管舒张活性。
表2受试样品舒张大鼠CA/BA的EC50
结论总结
人参二醇和人参三醇及其PCC氧化产物均具有舒张SD大鼠心脑血管的作用,在舒张BA、CA活性中,人参三醇的EC50值(15.65umol/L、5.59umol/L)最低,均低于人参二醇,并且在舒张BA活性中,人参三醇PCC产物的EC50值低于人参二醇,都在8umol/L左右,数值相对稳定。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.一种人参二醇、人参三醇的PCC氧化产物的应用,其特征在于:治疗心脑血管疾病药物的应用。
2.根据权利要求1所述的一种人参二醇、人参三醇的PCC氧化产物的应用,其特征在于:药物浓度为0.1—1000μmol/L。
3.根据权利要求2所述的一种人参二醇、人参三醇的PCC氧化产物的应用,其特征在于:药物浓度为8umol/L。
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